Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from conserved lysine residues in histones' amino terminal tails. They are found in all eukaryotic organisms and are believed to have a key role in the regulation of gene transcription. Importantly, recent studies suggest that HDACs are critically involved in cell cycle regulation, cell proliferation, differentiation, and the development of human cancer. The human class I HDACs, which possess homology to the yeast RPD3 protein, include HDAC1, HDAC2, HDAC3, and HDAC8. Although HDAC1, HDAC2, and HDAC3 have been extensively characterized, almost nothing is known about the functions, mechanisms of action, and regulation of HDAC8. In this proposal, the overall hypothesis is that, like other class I HDACs, HDAC8 plays an indispensable role in gene regulation. The long-term goal of this project is to obtain a greater mechanistic understanding of how HDAC8 regulates many cellular processes and how HDAC8 itself might be intricately regulated. Particular emphasis will be devoted to a detailed structure-function analysis of the HDAC8 protein and to the elucidation of how phosphorylation of HDAC8 by cAMP-dependent protein kinase A alters its activity. Additionally, genes that are regulated by HDAC8 will be rigorously identified. Given the importance of HDACs in health and disease, a thorough understanding of HDAC8 will not only increase our knowledge of chromatin structure and gene control, but will contribute directly to our overall understanding of normal and abnormal cellular processes. [unreadable] [unreadable]